Role of magnesium in the pathogenesis of hypertension
Introduction
Essential hypertension is a major modifiable risk factor for cardiovascular disease, such as cardiac failure, ischemic heart disease, stroke and end-stage renal disease. It develops as a result of complex interactions between susceptibility genes and environmental factors, which influence neural, humoral, cellular and subcellular mechanisms that regulate blood pressure (Carretero and Oparil, 2000). The basic hemodynamic abnormality in hypertension is increased peripheral resistance, due mainly to decreased lumen size of resistance arteries. Since resistance (R) is inversely proportional to the fourth power of the radius (r) (R∝1/r4), small changes in arterial radius (lumen) will have significant effects on resistance. In hypertension small arteries undergo structural and functional changes, resulting in reduced lumen size and increased peripheral resistance. These changes include media thickening, caused in part by increased cell growth and extracellular matrix deposition, and altered vascular tone, due to increased contraction and/or decreased vasodilation. Vascular smooth muscle cells are the final common pathway for many of these dynamic changes in hypertension. Consequently, much research has focussed on elucidating physiological mechanisms and pathophysiological events that regulate growth and contraction of vascular smooth muscle cells in health and cardiovascular disease. Of the many factors implicated in these processes, magnesium may play a key role.
Magnesium is an essential element that has numerous biological functions in the cardiovascular system. At the subcellular level, magnesium regulates contractile proteins, modulates transmembrane transport of calcium, sodium and potassium, acts as an essential cofactor in the activation of ATPase, controls metabolic regulation of energy-dependent cytoplasmic and mitochondrial pathways, regulates oxidative-phosphorylation processes and influences DNA and protein synthesis (Cowna, 2000; Grubbs and Maguire, 1987). Small changes in extracellular Mg2+ levels ([Mg2+]e) and/or intracellular free Mg2+ concentration ([Mg2+]i) have major effects on cardiac excitability and on vascular tone, contractility and reactivity (Altura and Altura, 1995; Altura et al., 1991). Decreased magnesium levels enhance reactivity of arteries to vasoconstrictor agents, attenuate responses to vasodilators, promote vasoconstriction and increase peripheral resistance, leading to increased blood pressure. Elevated magnesium levels have opposite effects leading to vasodilation, reduced vascular tone and decreased blood pressure. Thus magnesium may be physiologically important in blood pressure regulation whereas changes in magnesium levels could contribute to pathological processes underlying hypertension. Epidemiological and experimental studies support a role for magnesium deficiency in the pathogenesis of hypertension, with reports demonstrating inverse correlations between magnesium levels and blood pressure, hypotensive actions of dietary magnesium supplementation and hypertensive effects of magnesium deficiency (Touyz et al., 1987; Resnick et al., 1997; Kesteloot and Joossens, 1988; Kisters et al., 1998; Kawano et al., 1998; Touyz et al., 1992; Geleinjoise et al., 1996; Sasaki et al., 2000; Sanjuliani et al., 1996). However the therapeutic value of magnesium in the management of essential hypertension is unclear, with results from clinical trials being heterogeneous and inconsistent. There is also much controversy regarding the clinical importance of modestly decreased or elevated serum levels of magnesium. Furthermore, although intracellular magnesium deficiency has been implicated in hypertension, the current data are conflicting. The present review discusses the role of magnesium in the regulation of vascular function and the implications in hypertension. In addition, alterations in magnesium homeostasis in the pathogenesis of hypertension and the putative role of magnesium as an antihypertensive modality in the therapeutic management of hypertension will be considered. Magnesium influences functions of many systems, however the present review focuses specifically on the cardiovascular system and implications in hypertension.
Section snippets
Magnesium homeostasis in cardiovascular cells
For magnesium to significantly modulate cellular events, magnesium itself must be regulated within the cell. Despite the fact that magnesium is the most abundant cytosolic divalent cation, little is known about intracellular magnesium homeostasis and transport and mechanisms controlling [Mg2+]i are poorly understood (Murphy, 2000). Magnesium is not a static ion. It moves between compartments and across membranes (Fig. 1). Magnesium enters cells along a concentration gradient (Flatman, 1991) and
Vascular changes in hypertension––role of magnesium
Hypertension is due primarily to increased peripheral vascular resistance that is associated with functional, structural and mechanical alterations in the peripheral vasculature (Korner et al., 1989; Folkow, 1990; Mulvany and Aalkjaer, 1990) (Fig. 2). Functional alterations that increase peripheral resistance, include enhanced vascular reactivity to vasoconstrictor agents or impaired vasodilation and reflect changes in excitation–contraction coupling and/or electrical properties of cells (
Regulation of vascular tone and reactivity by magnesium
It has long been recognized that the concentration of extracellular magnesium influences blood flow, vascular reactivity and blood pressure in mammals. Processes by which magnesium influences hemodynamics leading to increased blood pressure are shown in Fig. 3. Hazard and Wurmser demonstrated in 1932 that increased serum magnesium produces significant vasodilation and hypotension (Hazard and Wurmser, 1932), whereas hypomagnesemia is associated with vasoconstriction and elevated blood pressure.
Magnesium and endothelial function
In addition to direct actions on vascular smooth muscle, magnesium modulates endothelial function (Altura and Altura, 1987). The vascular endothelium plays a fundamental role in the regulation of vasomotor tone by releasing nitric oxide (NO), ET-1, cyclo-oxygenase-derived prostanoid(s) such as prostacyclin (PGI2), and endothelial-derived hyperpolarizing factor. Intraarterial magnesium infusion increases endothelial-dependent vasodilation in human forearm (Haenni et al., 2002). These effects
Hypomagnesemia in experimental hypertension
Hypomagnesemia and decreased tissue content of magnesium have been demonstrated in various experimental models of hypertension (Laurant and Berthelot, 1992; Laurant and Berthelot, 1994; Mahboob et al., 1996; Berthelot et al., 1987; Laurant et al., 1995; Jones et al., 1988). The intracellular concentration of free magnesium is lower in isolated cardiomyocytes, striated and vascular smooth muscle cells from SHR, as well as in circulating cells from SHR, deoxycorticosterone acetate (DOCA)-salt
Epidemiological studies
Epidemiological studies have linked hypertension and hypertensive heart diseases, as well as ischemic heart diseases, with ‘soft water’, low in Mg2+, and protection against cardiovascular disease with ‘hard water’, high in Mg2+ (Elwood and Pickering, 2002). The best epidemiological evidence linking magnesium and blood pressure comes from the Honolulu Heart study (Joffres et al., 1987), in which the relationships of various dietary variables with blood pressure were examined. Of all the
Magnesium and pre-eclampsia/eclampsia
Pre-eclampsia, defined as hypertension after 20 weeks of gestation, with proteinuria (Shear et al., 1999), has been treated with magnesium salts since the turn of the century. During pre-eclampsia, both cardiac output and plasma volume are reduced whereas systemic vascular resistance is increased (Shear et al., 1999; Robert and Redman, 1993). These changes result in reduced perfusion of the placenta, kidney, liver and brain, leading to maternal and foetal morbidity and mortality (Robert and
Conclusions
The major hemodynamic abnormality in hypertension is increased peripheral resistance, due to changes in vascular structure and function. These changes include arterial wall thickening, altered vascular tone and impaired endothelial function and are influenced by multiple factors, including magnesium. At the cellular level there is increased vascular smooth muscle cell growth, increased extracellular matrix deposition, increased contractility and decreased dilation. Perturbations in magnesium
Acknowledgments
The author’s work cited in the review was supported by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Hypertension Society and the fonds de la recherche en sante du Quebec.
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